title: Divergent synthesis of 4-epi-fagomine, 3,4-dihydroxypipecolic acid, and a dihydroxyindolizidine and their β-galactosidase inhibitory and immunomodulatory activities.
abstract: A divergent asymmetric synthesis of the titled iminosugars has been formulated starting from a chiral homoallyl alcohol as the versatile intermediate. The homoallyl alcohol was prepared by a highly diastereoselective Barbier reaction on a d-glucose-derived aldehyde. The protection of its hydroxyl function followed by reductive ozonolysis of the olefin and a subsequent one-pot three-step protocol involving a Staudinger reaction, reductive amination, and benzyloxy carbonyl protection yielded an important bicyclic furanopiperidine derivative. This was converted to the target compounds by following standard reactions. Among the synthesized compounds, 4-epi-fagomine (2b) was the best β-galactosidase inhibitor, and it also prevented LPS-mediated activation of Raw 264.7 macrophage cells. Its congener, 3,4-dihydroxypipecolic acid (4b) also showed similar trends in its cytokine- and enzyme-inhibitory properties at a low concentration (10 μM) but was proinflammatory at higher concentrations. The bicyclic compound dihydroxyindolizidine (21) reduced the proinflammatory cytokine (IL-1β and TNF-α) levels in the LPS-activated Raw 264.7 cells without showing any enzyme-inhibition activity.
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400085, India.
authors.forename: K S Ajish
authors.initials: KS
authors.lastname: Kumar
authors.forename: J S
authors.initials: JS
authors.lastname: Rathee
authors.forename: M
authors.initials: M
authors.lastname: Subramanian
authors.forename: S
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D000818:Animals; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050112:Imino Pyranoses / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008968:Molecular Conformation; D010875:Pipecolic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C586490:3,4-dihydroxypipecolic acid; D016207:Cytokines; D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D050111:Imino Sugars; D007155:Immunologic Factors; D008070:Lipopolysaccharides; D010875:Pipecolic Acids; C105643:fagomine; D001616:beta-Galactosidase